Biopharmaceuticals have become an increasingly important part of modern medicine. The production of these biopharmaceutical drugs poses unique challenges. These products are in general obtained by culturing a host cell in a bioreactor to produce the drug substance of interest, followed by a number of liquid treatment steps such as clarification of the cell culture, filtration and chromatography steps. Effective liquid handling thus is a major requirement for any system that processes these products. Many workflows are also required to be run under controlled and contained conditions, which may involve aseptic handling in closed fluid handling systems and the use of pre-sterilized components, which is another major requirement for such systems.
Recently, automated biological liquid handling systems based on single-use flow paths have become available on the market. Single use flow path components offer the advantage that time- and labor consuming pre- and post-use cleaning of the wetted flow path is eliminated, thus increasing overall process efficiency and thereby reducing cost. The elimination of equipment cleaning and associated cleaning validation also greatly reduces the risk for cross-contamination in between different campaigns and drug substances, thus increasing overall process and drug safety. As the single-use components are utilized as consumables that are to be disposed after a process run or campaign, a design of systems and consumables to achieve overall cost efficiency and flexibility is a key interest to suppliers, users in the biopharma industry and eventually patient care. Flexibility is required to adapt the system and its single-use components to the liquid processing task of interest, such as for example chromatography, filtration etc. Depending on the sample and the specific process regimes required, flexibility is also required with regard to specific configuration within a selected processing task. A chromatography separation task may for example involve a larger or smaller number of inlets, outlets and components required, such as sensors, pumps etc.
ÄKTA ready (GE Healthcare) is a single-use liquid chromatography system built for process scale-up and production for early clinical phases. The system is intended to be used with ready-to-use, disposable flow paths that are deployed as consumables and disposed of after processing. The system uses 18 re-usable pinch valves installed in a fixed pattern at the instrument to manage fluid control in an interchangeable, single-use fluid path assembly. Flexible tubing of the fluid path assembly is fitted to the re-usable pinch valves according to a fixed installation scheme. The tubing and flow path is removed after processing to allow for disposal and installation of a new flow path.
The ÄKTA ready system controls the pinch valves with a “pneumatic distributor” mounted inside the instrument, the pneumatic distributor comprising a common air inlet for pressurized air and a control valve arrangement distributing and regulating the air pressure towards the pinch valves for control of the process liquid at side of the consumable, the single-use flow path. Each pneumatic pinch valve is connected via a pneumatic conduit to its respective control valve at the pneumatic distributor in a fixed configuration and layout.
Millipore's FlexReady chromatography system uses a “clamshell” design, which is a cassette comprising the consumable flow path, which is made up from a flexible bag with welded conduits forming the flow path. The clamshell also comprises required valving to open or close the fluid conduits of the disposable parts. Further, the clamshell comprises the “pneumatic distributor” that controls the pressurization of the fluid driven (pneumatic) valves controlling the flow of process liquid inside the conduits of the single-use consumable. The “pneumatic distributor” is again a control valve arrangement fed by a common pressurized air supply. The clamshell is interchangeable and different clamshells configured for different unit operations such as chromatography or filtration can be fitted to the instrument. In this regard, flexibility is provided to adapt to different liquid processing tasks by replacement of the clamshell. Each clamshell is however dedicated to a specific configuration of the consumable that is used for example for either chromatography or filtration. Therefore, the pneumatic controller in the clamshell will operate solely the specifically configured clamshell, other clamshells do require their own pneumatic distributor. Further, the pneumatic distributor in a given clamshell is configured to solely interact with and control the valve arrangement for a specific configuration of the single-use fluid flow path, the consumable. This design has also a need for multiple, fixed configured pneumatic distributors, which will impact overall cost of system hardware, complexity, as well as weight, size and ease of use for each clamshell. See WO2011154885 and US20130240065A1.
Pneumatically controlled valve arrangements have also been proposed for simulated moving bed chromatography. Examples of such valves are described in U.S. Pat. No. 7,846,335B2, U.S. Pat. No. 8,196,603B2 and U.S. Pat. No. 7,790,040B2.
US20110005984A1 proposed a two part valve. A separate, and potentially single-use valve part contacts the medium, and a reusable pneumatic actuator forms a separate part that is positioned adjacent to the valve part. The two parts may be connected to become a working valve. These valve arrangements are however bulky and inflexible as the seizing and positioning of the consumable parts and flow conduits adjacent to the latter cannot be selected independently from the size, position or configuration of the pneumatic actuator part.
While the fixed configurations in between valve manifolds and their pneumatic control systems described above is industry standard for single-use biological liquid processing systems, there are a number of disadvantages of fixed configurations with regard to limited flexibility, increased cost and a large physical size and weight involved in handling of the systems and its single-use consumables.
There is a need for better valve design that offers low cost and high flexibility for biological liquid handling, especially for the production of biopharmaceuticals.